Extending the dose schedule (from 4 weeks to 5 to 8 weeks) did not reduce efficacy and was not associated with progressive multifocal leukoencephalopathy, as shown in a retrospective analysis involving 1964 individuals (meeting report, April 2015)

Marketing applications for first-line use in anti-JC virus antibody negative MS patients have been submitted to the US Food and Drug Administration and the European Medicines Agency by Biogen Idec and Elan (16 January 2013)

Full rights for and control of Tysabri will be acquired by Biogen Idec from Elan Pharmaceuticals for cash ($3.25 billion) and future contingent payments; the deal is expected to close by the end of the second quarter of 2013 (6 February 2013)

Induces the production of antibodies against natalizumab in over half of treated patients (most of whom later revert to negative status for these antibodies); high titers of such antibodies (and corresponding low serum natalizumab concentrations) are associated with reduced efficacy of the drug

T cells from individuals under long-term treatment display enhanced rolling mediated by P-selectin glycoprotein ligand-1, as well as some adhesion, on primary human endothelial cells in vitro, even with blockade of very late antigen-4

TH17 cells [which express myeloma cell adhesion molecule (MCAM)] from individuals under long-term treatment still adhere to primary human endothelial cells in vitro; such adhesion is not prevented by blockade of very late antigen-4 (VLA-4), but is prevented if by blockade of VLA-4 and MCAM

Reduces counts of leukocytes, CD4+ and CD8+ T cells, B cells, and plasma cells in the cerebrospinal fluid in MS patients, in agreement with the idea that the drug weakens immune surveillance in the central nervous system

Treatment (every 4 weeks for 48 weeks) strongly increases peripheral CD4 counts, which then decline to baseline when treatment is interrupted (for 12 weeks), and then rise again when treatment is reinitiated, as shown in a study of individuals with relapsing MS

Associated with a reduction in the percentage of CD4+ T cells that express L-selectin that is apparent in the first year of treatment, persists, and then reverses when treatment ends, as shown in a longitudinal study

Selectively increases levels of effector-memory T cells in the blood, but does not affect the activation state of T cells in the blood, and does not selectively increase myelin-reactive T cells, in MS patients

Treatment is associated with downregulation of the microRNA miR-126 (a non-coding RNA that reduces expression of target genes) and upregulation of proteins POU2AF1 and Spi-B; POU2AF1 regulates Spi-B, a transcription factor that interacts with promotor/enhancer sequences of the JC virus (the cause of progressive multifocal leukoencephalopathy)

Associated with the presence of JC virus DNA in circulating CD34+ stem cells and CD19+ (B lymphocyte) cells (as well as higher levels of CD34+ cells, which are mobilized by natalizumab into the peripheral circulation) in a prospective study that compared individuals with MS beginning or undergoing natalizumab treatment with healthy volunteers, providing a link between the effects of natalizumab and progressive multifocal leukoencephalopathy

May counteract the altered metabolism of amyloid precursor protein (APP) that occurs in MS [which results in reduced levels of amyloid beta and soluble APP fragments in cerebrospinal fluid (CSF)], as determined by analysis of CSF samples from MS patients at baseline and after 1 to 2 years of treatment

Reduces expression of endogenous retroviruses of the HERV-W family, which have been linked with MS pathogenesis, as shown in a longitudinal cohort study of individuals with MS (none of whom relapsed during this study)

Reduces the antibody response against the human endogenous retrovirus HERV-Wenv(73-88) peptide (but not the response to peptides from Epstein Barr virus or Mycobacterium avium ss. Paratuberculosis) in individuals with MS after two years of treatment

Decreases the surface expression of CD49d (integrin α4) by causing the rapid internalization and degradation of CD49d, based on experiments using the human CD4+ T cell line Jurkat and human peripheral blood mononuclear cells

Reduces levels of chitinase-3-like protein 1, as well as the inflammation-related proteins Ig mu chain C region and haptoglobin, in the cerebrospinal fluid of RRMS patients, as shown by profiling proteomics experiments

Appears to increase the anti-JC virus antibody titer substantially over time, as shown in a longitudinal study involving 485 natalizumab-treated indivduals with MS, 340 of whom had repeat antibody testing

Induces the production of anti-natalizumab antibodies (which are associated with reduced drug efficacy) in a subset of patients soon after treatment onset (most commonly, within 1 month); in a study of 134 MS patients, 15.7% produced antibodies, with 8.2% persistently positive

Increases the absolute numbers of cells in all primary lymphocyte populations in the blood, especially natural killer cells and B cells, as shown by studies of individuals with RRMS before and after 1 year of treatment

Increases the proportion of memory and presumed regulatory B cell subsets and CD3(-)CD56(dim) cytotoxic natural killer cells in the blood lymphocyte population, but decreases the proportion of CD3(-)CD56(bright) regulatory natural killer cells, as shown by studies of individuals with RRMS before and after 1 year of treatment

Reduces the peripheral blood population of CD49d+ (α4 integrin subunit+) T cells, and this reduction is greater for regulatory T cells versus Th1 or Th17 cell subsets, as shown in a study of 27 natalizumab-naïve and 8 natalizumab-treated individuals with MS

Increases the expression of proinflammatory genes (TBX21, RORC, interferon γ, and interleukin 17A) and reduces the expression of FOXP3 in CD49d+ memory CD4 T cells, as shown in a study of sorted cells from natalizumab-naïve and natalizumab-treated individuals with MS

Increases the proportion of Th17 cells in peripheral blood, and this proportion falls to baseline when natalizumab is withdrawn (and becomes nearly undetectable during relapses that occur during washout), as shown in a study of 57 individuals with MS

Reduces the frequency of circulating plasmacytoid dendritic cells by 25 to 50%, but does not affect the frequency of myeloid dendritic cells, in individuals with MS, as shown by a cross-sectional observational study

Reduces the frequency of circulating plasmacytoid dendritic cells (PDCs) in individuals with MS; the PDCs present exhibit a mature, activated phenotype as compared with those from untreated individuals, as shown by a cross-sectional observational study

Increases the number of circulating hematopoietic stem and progenitor cells in some individuals, and this phenomenon is associated with clinical remission as well as an increased frequency of B cells and regulatory T cells

Increases the mean total white cell, lymphocyte, and eosinophil counts in peripheral blood by month 1, and these counts then remain at these higher levels, as shown in an 18-month longitudinal study of 44 individuals with RRMS

Decreases levels of neurofilament heavy and light chain (markers of axonal damage) in cerebrospinal fluid in RRMS patients, such that the effect is more pronounced for the light chain; in patients in remission, the effect was significant for the light but not heavy chain

Reduces levels of lipocalin-2, which is increased in progressive MS (and has been shown in inhibit remyelination in rat cultures), in the cerebrospinal fluid, as shown in a 60-week study of 17 individuals with this condition

Reduces concentrations of 24S-hydroxycholesterol in the serum, and these serum concentrations correlate with scores on the Symbol Digit Modalities Test (a measure of cognition) before and after treatment, as shown in a 12-month study of 31 individuals with RRMS

Effectiveness is not increased in patients carrying the CCR5 delta32 deletion allele versus those who do not; this idea was tested because CCR5 (a chemokine receptor) might play a role in recruiting T cells to the central nervous system in MS

In individuals switching from natalizumab to fingolimod, a low saturation (<30%) of natalizumab on the surface of CD8+ and CD4+ T cells before beginning fingolimod is associated with disease activity during a 6-month followup, whereas higher levels (66 to 70%) are associated with absence of disease, based on a pilot study of 5 individuals with MS

Improves performance in walking-related parameters when individuals are asked to walk and perform a cognitive task at the same time, but does not improve such parameters when walking is the only task being performed, based on a study of 9 individuals with MS over 1 year

Treatment results in sustained disability improvement in ~30% of individuals with MS, as well as a reduction in the MRI lesion burden; the improvement in disability is associated with shrinkage of the T1 lesion volume

Associated with a relative reduction of 42.8%% in the risk of ≥1 relapses during 2 years of treatment and is more cost effective than interferon beta-1a (Avonex or Rebif), interferon beta-1b (Betaferon), or glatiramer acetate, according to a pharmacoeconomic analysis that used pre-existing data

Effectiveness (measured in terms of a lack of relapses and disease progression) correlates with a decrease in the titer of IgG antibodies against human herpes virus 6A/B, whereas an increase predicts relapse, as shown in a 2-year longitudinal study

Early treatment is associated with an increase in the absolute concentration of N-acetylaspartate (a marker of neuronal integrity) and other brain metabolites in lesional white matter (where concentrations are reduced relative to normal white matter), potentially indicating increased axonal metabolism, as shown in a longitudinal study of individuals with RRMS

Induces lymphocytosis, and people who exhibit lower-than-expected lymphocytosis may have a higher risk of relapse, indicating that such natalizumab-induced lymphocytosis may be useful as a biomarker of therapeutic efficacy, as shown in a study of 50 individuals with RRMS or progressive-relapsing MS who had been given ≥16 natalizumab infusions

Appears to reduce the high risk of post-partum relapse when restarted soon after delivery (on average, 7.8 days later) in women who had stopped therapy during pregnancy, as shown in a retrospective analysis of 6 women with very active MS in whom disease activity disappeared in all but 1 of them after such early redosing

Does not affect the response to immunization with either a recall antigen (tetanus toxoid) or a neoantigen (keyhold limpet hemocyanin) in a clinically relevant manner, on the basis of a study of 60 individuals with RRMS, 30 who were natalizumab-naïve and 30 who had received 6 months of natalizumab treatment

Does not impair the function of CD4+ CD8+ T cells, which are present in the circulation at similar frequencies in individuals with and without MS; the cells are also present in the cerebrospinal fluid, but not in inflammed MS lesions

Treatment can be associated with a transient reactivation of Epstein-Barr virus (EBV), but EBV-specific antibody levels do not appear to be useful as a biomarker for therapeutic natalizumab response, as shown in a 21-month study of 20 individuals with MS

Does not affect the percentage of circulating 6-sulfo LacNAc(+) dendritic cells, proinflammatory cells that are present in demyelinated brain lesions and are often present in cerebrospinal fluid in individuals with MS

Reduces levels of lipocalin 2 in the cerebrospinal fluid (CSF) and astrocytes in a mouse experimental autoimmune encephalomyelitis model; lipocalin 2 expression is upregulated in CSF in this model and in MS patients

Antibodies against α4 integrin (i.e., not natalizumab per se) suppress experimental autoimmune encephalomyelitis (EAE) in wild-type mice, whereas they do not suppress EAE in mice deficient for epithelial V-like antigen (which develop more severe EAE than wild-type mice), suggesting that EVA expression is needed for the best therapeutic response to these antibodies

Antibodies against α4 integrin (i.e., not natalizumab per se) reduce the frequency of mature B lymphocytes (as well as T lymphocytes) in the central nervous system in wild-type mice with experimental autoimmune encephalomyelitis (EAE), but not in EAE mice deficient for epithelial V-like antigen

Antibodies against α4 integrin reduce expression of chemokine SDF-1/CXCL12 and its receptor CXCR4 in an experimental autoimmune encephalomyelitis (EAE) model; both the chemokine and its receptor are upregulated in EAE

Extending the dose schedule (from 4 weeks to 5 to 8 weeks) did not reduce efficacy and was not associated with progressive multifocal leukoencephalopathy, as shown in a retrospective analysis involving 1964 individuals (meeting report, April 2015)

Associated with anaphylactoid reactions in some individuals; specific human leukocyte antigen (HLA) alleles (HLA-DRB1*13 and HLA-DRB1*14) were present at increased frequency in a group of 54 such individuals, whereas the HLA-DRB1*15 allele was present at increased frequency in a group of 65 who lacked such reactions, suggesting that HLA-DRB1 genotyping before natalizumab therapy could be useful

Three individuals with apparent granule cell neuronopathy (JC virus infection of cerebellar granule cell neurons, characterized by cerebellar atrophy) were identified among 44 individuals with natalizumab-associated progressive multifocal leukoencephalopathy (PML); no cases were found in a control group of 25 natalizumab-treated individuals without PML

Severe natalizumab-associated liver injury has been reported in 12 individuals and almost 30 cases of natalizumab-associated liver failure have been listed in the postmarketing US Food and Drug Administration's adverse event reporting system (November 2015)

Progressive multifocal leukoencephalopathy has been detected in a patient in which four samples of cerebrospinal fluid were negative for JC virus DNA, as assayed by PCR, but a brain biopsy eventually was shown to be positive, as assayed by immunohistochemistry

Presumptive progressive multifocal leukoencephalopathy has been detected in an RRMS patient 14 weeks after the discontinuation of natalizumab, after 36 months of therapy; cerebrospinal fluid was negative for JC virus

Increases the risk of progressive multifocal leukoencephalopathy (PML), but early detection of this condition (by brain scans and spinal fluid tests, before symptoms occur) may be associated with improved survival, as shown in an industry-sponsored study of 319 natalizumab-treated MS patients diagnosed with PML

Risk for natalizumab-associated progressive multifocal leukoencephalopathy (PML) is considered relatively low in patients testing negative for anti-JC virus antibodies, but about a third of MS patients (in a group of 49) who tested negative for such antibodies had active viremia, indicating they might in fact be at high risk for PML

Risk for natalizumab-associated progressive multifocal leukoencephalopathy (PML) is higher in patients who exhibit an increased anti-JC virus antibody index more than 6 months before the PML diagnosis (relative to those without a PML diagnosis)

Risk for natalizumab-associated progressive multifocal leukoencephalopathy may be further defined among individuals positive for anti-JC virus antibodies by the serum or plasma level of such antibodies (measured as an index); this idea would apply to individuals without prior immunosuppressant use

Associated with a risk of progressive multifocal leukoencephalopathy (PML); a very low percentage of L-selectin-expressing CD4+ T cells is highly correlated with a risk for PML, indicating a possible biomarker for risk

Associated with a risk of progressive multifocal leukoencephalopathy (PML); a correlation between the level of soluble L-selectin and the anti-JC virus antibody index in the sera of natalizumab-treated (but not interferon beta-treated) individuals with RRMS has been observed, indicating that soluble L-selectin might serve as a biomarker for PML risk

Associated with a risk of progressive multifocal leukoencephalopathy (PML); a single risk algorithm that incorporates both the anti-JC virus antibody index and L-selectin (CD62L) level may be useful for reducing the incidence of PML

A risk of natalizumab-associated progressive multifocal leukoencephalopathy (PML) is not predicted by the percentage of CD3+ CD4+ CD62L+ cells in cryopreserved peripheral blood mononuclear cells (PBMCs), as shown in a study of cell samples from 21 individuals treated with natalizumab who developed PML and 104 matched individuals who did not

Natalizumab-associated progressive multifocal leukoencephalopathy (PML) diagnosis might be improved by use of an anti-JC virus "antibody specificity index," a measure of the proportion of anti-JC virus antibodies in cerebrospinal fluid (CSF) versus serum (such that increased levels in CSF are associated with PML)

Estimated occurrence of progressive multifocal leukoencephalopathy (PML) among natalizumab-treated individuals with MS (with an average of 17 months of treatment) was 1 per 1000 in 2006; with more individuals receiving treatment for longer times, the occurrence is now about 1 per 330, but rises to 1 per 90 in those with additional PML risk factors (August 2013)

Risk for natalizumab-associated progressive multifocal leukoencephalopathy, based on the most recently available data, is higher in 2015 than in 2012, such that an individual with three risk factors (positive JC virus antibody status, >2 years of natalizumab therapy, and previous immunosuppressive therapy exposure) has ~1:44 chance of developing this disorder

Despite the increased risk of natalizumab-associated progressive multifocal leukoencephalopathy in individuals positive for JC virus antibodies, the decision to continue natalizumab treatment is largely unaffected by JC virus antibody status, based on a study of 112 individuals

Associated with progressive multifocal leukoencephalopathy (PML), but in one postmortem study of an individual with MS who developed PML after natalizumab therapy, the extensive PML lesions (which contained JC virus DNA), located in the neocortex and cerebral white matter, were distinct and separate from chronic inactive MS lesions nearby

Associated with progressive multifocal leukoencephalopathy (PML); in one individual with RRMS treated with natalizumab, brainstem lesions were first interpreted to be MS plaques, but later became confluent and were identified as a PML lesion

Occurrence of progressive multifocal leukoencephalopathy (PML) within 6 months after discontinuation of natalizumab for reasons not related to suspected PML has been documented in 17 patients, most (16) of whom were determined to have had at least 1 risk factor for PML at the time of natalizumab withdrawal

Association with a risk for progressive multifocal leukoencephalopathy has led to natalizumab's use as a second-line therapy; an algorithm has been developed to select individuals for whom use as a first-line therapy might be appropriate

Outcomes of either discontinuing natalizumab or obtaining additional screening in those at risk for natalizumab-associated progressive multifocal leukoencephalopathy have been described with decision tree models

Three factors (anti-JC virus antibodies, previous use of immunosuppressants, and length of natalizumab therapy) have been found to contribute to the risk of natalizumab-associated progressive multifocal leukoencephalopathy (PML), but risk stratification did not reduce the incidence of PML in natalizumab-treated individuals with MS in the period between April 2010 and February 2014

Associated with a risk of developing progressive multifocal leukoencephalopathy, especially in individuals seropositive for JC virus (JCV); individuals can be seronegative for JCV (based on serological tests) but still shed JCV DNA into the urine; furthermore, natalizumab might accelerate JCV shedding into the urine

Associated with progressive multifocal leukoencephalopathy (PML); the number of plasmapheresis/immunoadsorption treatments (important for PML outcome) required to reach subtherapeutic serum natalizumab concentrations varies depending on the serum natalizumab concentration at the time of PML diagnosis

Asymptomatic natalizumab-associated progressive multifocal leukoencephalopathy manifests as relatively localized disease on MRI, often affecting the frontal lobe, based on a study of 18 individuals with MS

Early natalizumab-associated progressive multifocal leukoencephalopathy (PML) with immune reconstitution inflammatory syndrome exhibits certain characteristics in MRI; the most common first sign is patchy or punctate contrast enhancement in the border of the PML lesion, based on a retrospective study of 26 individuals with MS

Natalizumab-associated progressive multifocal leukoencephalopathy (PML) is associated with a punctate pattern in MRI, as shown in a study of 20 individuals with PML, and this pattern might represent the first imaging feature detectable during presymmptomatic stages of PML

Natalizumab-associated asymptomatic progressive multifocal leukoencephalopathy (PML) is associated with certain features in MRI; the most predictive features are hyperintensity on diffusion-weighted images and U fiber involvement, as shown in a retrospective study of 11 individuals with MS with such a diagnosis and 40 individuals with MS treated with natalizumab but without PML

Natalizumab-associated progressive multifocal leukoencephalopathy (PML) is preceded by high serum anti-JC virus antibody indexes, although an increase just before PML diagnosis was not observed, as shown by a longitudinal study in 4 individuals with MS who developed PML

Survival and disability outcomes for individuals with natalizumab-associated progressive multifocal leukoencephalopathy (PML) are better for those who are asymptomatic at the time of PML diagnosis (by MRI and JC virus detection) than for those who are symptomatic

Progressive multifocal leukoencephalopathy (PML)-immune reconstitution inflammatory syndrome was diagnosed in an individual after the discontinuation of natalizumab (at which time PML was missed by MRI) and the initiation of fingolimod

Risk of natalizumab-associated progressive multifocal leukoencephalopathy (PML) is lower in individuals with lipid-specific IgM oligoclonal bands in cerebrospinal fluid (a marker of highly inflammatory MS), as shown in a study of 24 individuals who developed PML and 343 who did not

Survival of natalizumab-associated progressive multifocal leukoencephalopathy is more likely in those who are younger at diagnosis and have lower Expanded Disability Status Scale scores before diagnosis, lower loads of JC virus in the cerebrospinal fluid at diagnosis, less functional disability in general, and localized rather than widespread disease at diagnosis as assessed by MRI, as shown in a study of 336 individuals, 76% of whom survived this condition

Risk of natalizumab-associated progressive multifocal leukoencephalopathy might be lower in pediatric versus adult MS patients, because the seroprevalence of JC virus antibody is lower in this pediatric population (33.3%) than reported in adults (60%), as shown in a study of 109 pediatric MS patients

In a case of severe natalizumab-associated progressive multifocal leukoencephalopathy (PML), four neurotropic variants of the JC virus were detected in blood cells, serum, and urine, suggesting that detection of such a variant in blood might aid in the prevention of severe PML

Natalizumab-associated progressive multifocal leukoencephalopathy (PML) has been reported in an individual using extended dosing intervals (300 mg every 6 weeks), a method that has been suggested for lowering the risk of PML

Natalizumab-associated early progressive multifocal leukoencephalopathy (PML) lesions were distinguished from MS lesions by 7T MRI in a case in which PML and ongoing MS activity presented simultaneously

Associated with a high annualized rate of seroconversion for anti-JC virus antibodies (7.1%, with a cumulative seroconversion rate of >25% over 4 years), as shown in a Dutch cohort of 179 individuals with RRMS; such seropositivity is a risk factor for natalizumab-associated progressive multifocal leukoencephalopathy

Might increase seroconversion to positive JC virus antibody status, and increase JC virus index values, as shown in a study of 525 German and 711 French individuals with MS who were followed longitudinally (such that 10.3% of the German group and 8.5% of the French group converted per year); such seropositivity is a risk factor for natalizumab-associated progressive multifocal leukoencephalopathy

Might increase the risk of subclinical varicella-zoster virus (VZV) reactivation or reinfection, based on the increased incidence of elevated levels of anti-VZV IgG in natalizumab-treated individuals with MS

Cessation of natalizumab [to avoid risk of progressive multifocal leukoencephalopathy (PML) or because PML was detected] was associated with immune reconstitution inflammatory syndrome in four cases; the case in which no PML was detected was fatal

End of dosing cycle is associated with a return of MS symptoms (such as fatigue, weakness, impaired walking, and difficulties with cognition) in about two thirds of those receiving treatment, based on a study of 100 individuals; such symptoms began a median of 21 days after infusion

Discontinuation during pregnancy was associated with a strong increase in disability and a high load of MRI lesions in 4 women with MS, despite the fact that pregnancy is generally associated with disease stability

Discontinuation due to pregnancy leads to strong rebound activity (resulting in a relapse rate of 32.2% in this study), indicating that the protective effects of pregnancy do not extend to this situation, based on an analysis of 59 women who discontinued natalizumab during pregnancy (meeting report)

Cessation of treatment is followed by relapses (with a cumulative probability of 52.9% in the year after cessation) associated with abnormal inflammatory activity (>5 gadolinium-enhancing lesions, exceeding the number before treatment), as shown in a study of 32 individuals with MS

Each of two episodes of natalizumab discontinuation in a study of 15 individuals was followed by disease reactivation, despite immunomodulant treatment (after the first withdrawal) or a second-line therapy such as fingolimod (after the second withdrawal)

After natalizumab withdrawal, significant clinical worsening is associated with a higher Expanded Disability Status Scale (EDSS) score at baseline and with a 1-step increase in the EDSS during treatment

Treatment discontinuation (as a result of concerns about the risk of progressive multifocal leukoencephalopathy) is associated with a 1 in 3 risk of disability worsening, and that risk increases to 1 in 2 if the Expanded Disability Status Scale Score is >3 when treatment begins, based on a study of data from 318 individuals who did not exhibit worsening disability in the first 2 years of treatment and a followup time of 6 years

Discontinuation is followed by a period of high risk for disease activation (between the second and eighth months), during which most individuals return to pre-natalizumab levels of disease activity and 10% exhibit rebound activity, and neither immunomodulant therapy nor fingolimod protects sufficiently against this activity, based on a study of 110 individuals

Marketing applications for first-line use in anti-JC virus antibody negative MS patients have been submitted to the US Food and Drug Administration and the European Medicines Agency by Biogen Idec and Elan (16 January 2013)

Full rights for and control of Tysabri will be acquired by Biogen Idec from Elan Pharmaceuticals for cash ($3.25 billion) and future contingent payments; the deal is expected to close by the end of the second quarter of 2013 (6 February 2013)

Company-sponsored, multicenter, randomized, double-blind, placebo-controlled trial to determine the optimum timing for beginning fingolimod treatment after discontinuation of natalizumab; individuals who had been treated with natalizumab for at least 6 months (and had reason to discontinue such as positive JC virus antibody status, a risk for progressive multifocal leukoencephalopathy) were randomized to the following regimens: a washout period of 8 weeks followed by 24 weeks of fingolimod, a washout period of 12 weeks (no therapy for 8 weeks followed by 4 weeks of placebo) followed by 20 weeks of fingolimod, or a washout period of 16 weeks (no therapy for 8 weeks followed by 8 weeks of placebo) followed by 16 weeks of fingolimod; the primary outcome was the number of active T2 lesions during the washout and first 8 weeks of fingolimod; brain MRIs were obtained at baseline and weeks 8, 12, 16, 20, and 24

8- and 12-week washout periods were associated with fewer active T2 lesions during washout and the first 8 weeks of fingolimod (2.1 and 1.7 versus 8.2 for the 16-week washout) and a higher percentage of relapse-free individuals (88% and 91% versus 84% for the 16-week washout) during the 24 weeks since the last natalizumab treatment

Industry-funded, randomized, partially placebo-controlled exploratory study to examine disease activity in individuals who had been treated with natalizumab (with no relapse activity during the previous year and no gadolinium-enhancing lesions at the time of screening) during an interruption of natalizumab treatment; participants received either natalizumab, interferon beta-1a, glatiramer acetate, methylprednisolone, or placebo during the interruption

Interruption in natalizumab treatment was associated with an increased risk of MRI and relapse activity even when other therapies were used; relapses occurred in 4% of participants receiving natalizumab versus 15% to 29% of participants in other arms of the study

; during the randomized treatment period, gadolinium-enhancing lesions were observed in 0% of individuals receiving natalizumab, 48% of those receiving other treatments, and 61% of those on placebo; such lesions were primarily observed at week 16 or later

Industry-sponsored, multinational, randomized, double-blind, placebo-controlled study to examine the efficacy of intravenous natalizumab (300 mg every 4 weeks) on slowing disability accumulation that is not related to relapses, as measured by the Expanded Disability Status Scale or other tests (primary outcome measure)

Industry-sponsored, multinational, randomized, placebo-controlled trial to study the efficacy and safety of natalizumab (300 mg, intravenous infusion every 4 weeks), with the primary endpoint at one year being the rate of clinical relapse and the primary endpoint at two years the cumulative probability of sustained progression of disability, measured by the Expanded Disability Status Scale (EDSS) score

; posthoc analysis showed that the drug increased the probability of a lack of evident disease activity (clinically or detected by MRI) in all individuals, but this effect was greater in individuals with an EDSS score <3.0 versus those with a score ≥3.0 at baseline; additional posthoc analysis showed that natalizumab reduced the severity of relapses

; retrospective analysis of treated versus control individuals showed that natalizumab was associated with an increase in the proportion of individuals who exhibited ≥20% improvement in timed 25-foot walk speed at year 2

; posthoc analysis showed that natalizumab decreased relapse severity (with a mean increase in the EDSS score of 0.77 for the natalizumab group and 1.09 for the placebo group at relapse) and improved recovery from relapse-associated disability, as measured by changes in the EDSS score

Industry-sponsored, multinational, randomized, double-blind, placebo-controlled, parallel-group trial to determine if natalizumab (300 mg intravenously every 4 weeks) together with interferon beta-1a (30 microg intramuscularly every week) is more effective than interferon beta-1a alone in reducing breakthrough disease activity in patients who had received interferon beta-1a treatment for at least 12 months before randomization in study (with at least one relapse in the 12 months before randomization), with the rate of clinical relapse at 1 year and the cumulative probabilty of disability progression at 2 years the primary end points

Combination therapy was associated with a 23% cumulative probability of sustained disability progression at 2 years versus 29% with interferon beta-1a alone; combination therapy reduced the risk of sustained disability progression by 24% and reduced the annualized rate of relapse by 54% (at 1 year) and 55% (at 2 years) as compared to interferon beta-1a alone; trial was stopped 1 month early because of two cases of progressive multifocal leukoencephalopathy, one of which was fatal

Company-sponsored, multinational, randomized, placebo-controlled trial to test the efficacy of natalizumab (3 mg or 6 mg per kg of body weight every 28 days, by intravenous infusion) in reducing the number of new gadolinium-enhancing brain lesions (primary end point)

Multicenter, observational, French study to compare the effects of natalizumab and fingolimod on relapses and MRI outcomes, with statistical analysis done using both logistic regression and propensity scores

The group receiving natalizumab had a lower proportion of participants with ≥1 relapse than the group receiving fingolimod at year 1 (confounder-adjusted proportion, 21.1% versus 30.4%) and year 2 (30.9% versus 41.7%) as well as a lower proportion with new T2 and gadolinium-enhancing lesions at both 1 and 2 years

Prospective, randomized, rater-blinded, parallel-group study to examine treatment satisfaction in individuals who had been treated with intravenous natalizumab (300 mg monthly) for at least 12 months (and had increased risk or fear of progressive multifocal leukoencephalopathy), who were then randomly assigned to either subcutaneous interferon beta-1b (250 microg every other day) or continued natalizumab treatment

Real-life observational study in Denmark to compare clinical disease activity between individuals treated with natalizumab versus fingolimod; individuals who began treatment either of these drug as their first second-line treatment between July 2011 and March 2015 were prospectively recorded in the Danish MS Treatment Register and the two groups were 1:1 propensity score matched

Differences in clinical disease activity were not found between the two treatment arms: for natalizumab, the annualized relapse rate (ARR) was 0.296 and the mean time to first relapse was 2.55 years; for fingolimod, the ARR was 0.307 and the mean time to first relapse was 2.56 years; Expanded Disability Status Scale score change did not differ between the groups

Observational study to compare the outcomes for individuals switching, because of positive anti-JC virus antibody status, from natalizumab to either rituximab or fingolimod at three Swidish centers (which had different preferences for rituximab and fingolimod)

Continuous, longer natalizumab use was associated with a lower relapse rate; disability status was generally stable in the continuous group (with progression occurring in 8% of this group), whereas disability progression occurred in 37% and 35% of participants in the non-continuous and discontinuation groups, respectively; accumulation of lesions and brain atrophy did not differ with respect to natalizumab duration

The annualized relapse rate (ARR) did not increase as the interval between doses increased, such that ARRs were 0.14 and 0.09 for the SID and EID groups, respectively, and similar proportions of individuals in the SID and EID groups exhibited no evidence of clinical or radiographic disease activity; PML did not occur in the EID group, whereas 4 cases occurred in the SID group

Peak serum concentrations of natalizumab after SC or IM administration were 40% the level seen after IV administration; mean bioavailability after SC or IM administration was 57.1-71.3% and 48.7%, respectively, relative to IV administration; the pharmacodynamic response and incidence of adverse events and anti-natalizumab antibodies were similar following each type of administration

Single-blinded, randomized study to compare the effects of immediate versus tapered down natalizumab cessation; those in the immediate discontinuation group stopped natalizumab immediately and began another disease modifying therapy after the last infusion of natalizumab, whereas those in the tapered down group received natalizumab infusions spaced 6 and 8 weeks apart before beginning another therapy

Discontinuation of natalizumab was associated with new disease activity, but those in the tapered down group exhibited fewer relapses (28 versus 8) and a lower number of new MRI lesions in the 12 months after the last infusion than those in the immediate discontinuation group

Retrospective review to examine risk factors for and frequency of MS disease reactivation after natalizumab discontinuation in two Italian centers, as well as the effects of disease modifying drugs (DMDs) on reducing the risk of such reactivation

Natalizumab discontinuation resulted in disease reactivation (relapses) in 54.4% of these individuals and rebound in 21.2%; reactivation and rebound were correlated with more frequent relapses before natalizumab began, fewer natalizumab infusions, and a longer washout period; after discontinuation, a lack of treatment was associated with more disease activity and rebound than DMDs, and second-line therapies (natalizumab and fingolimod) prevented relapses better than first-line therapies (interferon beta, glatiramer acetate, teriflunomide, and azathioprine) after natalizumab discontinuation

Alemtuzumab was found to be the most protective against relapses during the first 24 months of therapy (moderate quality evidence); the next most protective were found to be mitoxantrone (very low quality evidence), natalizumab (high quality evidence), and fingolimod (moderate quality evidence); mitoxantrone (low quality evidence) was found to be the most effective at delaying disability worsening, followed by alemtuzumab (low quality evidence) and natalizumab (moderate quality evidence); these results must be interpreted conservatively because few trials have been performed for most of the drugs

Natalizumab reduced the ARR by 91% and improved neurological disability; a larger effect was seen in individuals with an Expanded Disability Status Scale score <3.0 as compared with those with a score ≥3.0

Observational study to examine the long-term effects of natalizumab on cognition, with assessments at baseline and yearly thereafter; relapse number, Expanded Disability Status Scale (EDSS) score, and effects on cortical atrophy (in a subset of individuals) were also examined

Natalizumab treatment was associated with improvements in neuropsychological tests of memory, attention, and executive function; at 3 years, there was no change in gray matter volume, but parahippocampal and prefrontal gray matter density was increased; additionally, the annualized relapse rate was reduced at each time point as compared with baseline and the EDSS score was stable

Comparison of relapse rates and time to relapse, using US administrative claims data from the Truven Health MarketScan Research Databases and propensity score matching, in individuals treated with platform therapy (interferon beta or glatiramer acetate) or natalizumab

Natalizumab was associated with a reduced rate of relapse (which occurred in 26.5% of individuals in the natalizumab group and 35.5% in the platform group) and greater time to relapse (308 days for the natalizumab group and 283 days for the platform group)

Investigator-initiated, partly industry-supported, exploratory, open-label, monocentric study to examine immune cell migration and function and disease activity during a switch from natalizumab to fingolimod; participants (who had been receiving natalizumab treatment for ≥12 months) will receive a final natalizumab infusion, after which there will be an 8-week washout period followed by 24 weeks of fingolimod treatment

Industry-sponsored, randomized, prospective, dose-ranging, double-blind study to compare the effects of giving natalizumab via subcutaneous and intravenous routes [with 300 mg given either subcutaneously or intravenously every 4 or 12 weeks (with matching placebo during the intervening periods in the 12 week dosing groups); 150 mg was also given every 12 weeks by both routes], with the primary outcome measure the cumulative number of combined active lesions; blinding was to dose but not route of administration

Subcutaneous administration every 4 weeks appeared as effective as intravenous administration every 4 weeks (with breakthrough disease activity occurring in the groups receiving drug every 12 weeks); however, Biogen does not plan to attempt to commercialize the subcutaneous product (meeting report, June 2015)

Retrospective data collection and comparison of the annualized relapse rate (ARR), disability progression, and the number of new brain and spinal T2 lesions between matched individuals with spinal versus non-spinal MS before and after natalizumab treatment; multivariate regression models were used for the comparisons

Natalizumab was associated with similar reductions in ARR and the number of new brain and spinal T2 lesions in the two groups, but only significantly reduced disability progression in spinal MS (disability progression was similarly low in the two groups after treatment initiation, but higher in the spinal group before treatment)

Analysis of data from the MSBase registry and the TYSABRI Observational Program to compare the effects of switching to natalizumab versus switching between interferon beta and glatiramer acetate in individuals who experienced a relapse while on interferon beta or glatiramer acetate; datasets were propensity matched

Switching to natalizumab was associated with a reduction in annualized relapse rate in the first year by 65 to 75% and a reduction in the risk of confirmed disability progression over the first 24 months by 26% as compared with switching between interferon beta and glatiramer acetate

Retrospective analysis to examine differences in a real-world setting in baseline characteristics and drug discontinuation among individuals beginning treatment with natalizumab or fingolimod, who registered in a Swedish drug monitoring registry in 2011 to 2013

Those in the fingolimod group were older and more likely to be male than those in the natalizumab group; most [87% (natalizumab), 83% (fingolimod and natalizumab-naïve), and 76% (fingolimod after natalizumab)] continued on treatment after 1 year; individuals on fingolimod discontinued treatment because of adverse events more often than those on natalizumab

Natalizumab was effective in highly active RRMS, such that the annual relapse rate declined from a mean of 2.49 at baseline to 0.47 after 1 year and to 0.34 after 2 years; an Expanded Disability Status Scale score ≤3.0 at baseline correlated with freedom from disease activity

Retrospective review of the IMS PharMetrics Plus claims database (years 2006 to 2012) to examine the effects of persistent natalizumab use versus the effects of transitioning from persistent to nonpersistent use (and other treatment patterns) on annual relapses and relapse-related costs; persistence was defined as a lack of ≥90 day gaps in therapy

Treatment patterns that involved a transition from persistent to nonpersistent natalizumab use were associated with significant increases in annual relapses (mean relapse rate increase, 0.23) and relapse-related costs (mean increase, $1346), whereas those that involved a transition from nonpersistent to persistent use were associated with nonsignificant decreases in these measures

Analysis of data from the MSBase registry to compare the effects of switching to natalizumab versus fingolimod from interferon beta or glatiramer acetate (with the change in treatment made because of relapses or disability progression in the preceding 6-month period); subpopulations with comparable baseline characteristics were selected by using quasi-randomization with propensity score-based matching

Switching to natalizumab appeared more effective in decreasing the relapse rate and burden of short term disability than switching to fingolimod, such that the annualized relapse rate changed from 1.5 to 0.2 for natalizumab and from 1.3 to 0.4 for fingolimod and the rate of sustained disability regression was 2.8 times higher for natalizumab versus fingolimod, although the rate of sustained disability progression events was similar

Study to compare the cost-effectiveness of natalizumab versus fingolimod from a Swedish perspective, using data from the AFFIRM and FREEDOMS trials; the model considered costs of drug acquisition, administration and monitoring, and treatment of MS relapses

When all individuals with RRMS were considered, treatment with fingolimod was found to cost less but treatment with natalizumab resulted in more relapses avoided (0.74 versus 0.59); when only individuals with rapidly evolving severe disease were considered, natalizumab dominated fingolimod; natalizumab was found to be cost-effective in >80% of the simulations in both groups of individuals at a willingness-to-pay threshold of 500,000 Swedish kronor per avoided relapse

Gadolinium enhancement (inflammation) present at baseline was linked with greater decreases in brain volume during years 1 and 2 but not during year 3; furthermore, brain volume changes and disability status showed a marginal association at months 12 and 36

Natalizumab reduced the mean annualized relapse rate and Expanded Disability Status scale scores for individuals treated ≥12 months; the treatment was most effective in those who had not received other disease-modifying therapy and in those with less disability

Retrospective review of medical data from individuals treated with natalizumab, who had the opportunity to switch to extended interval dosing (EID, which is receiving the drug at 6 to 8 week intervals rather than 4 week intervals), a potential method of reducing the risk of progressive multifocal leukoencephalopathy; the aim of this study was to evaluate whether EID was linked with an increase in relapses

Retrospective analysis of prospectively-collected clinical and MRI data from individuals treated at one hospital in Italy to compare the effects of natalizumab versus fingolimod; individuals treated with natalizumab exhibited more active disease in the pretreatment period

Individuals treated with natalizumab had a lower risk of relapse than those treated with fingolimod (despite the higher baseline disease activity in those receiving natalizumab), but Expanded Disability Status Scale score and MRI outcomes were similar under the two forms of treatment

Prospective, controlled, observational study to assess the effects of fetal exposure to natalizumab during the first trimester; outcomes were compared to those from disease-matched (DM; treated or untreated with other disease-modifying drugs) and healthy control (HC) groups

Natalizumab exposure during the first trimester was not associated with increased risk of adverse outcomes relative to risks in the DM group; the rate of major malformations, low birth weight, and premature birth were similar among all three groups, whereas miscarriage rates were higher in the natalizumab and DM groups

Study to compare patient satisfaction with intramuscular interferon beta-1a, subcutaneous interferon beta-1a, glatiramer acetate, and natalizumab and to compare links between therapy adherence and satisfaction; the Treatment Satisfaction Questionnaire for Medicine and multivariable models were used

Overall, the drugs were associated with similar levels of satisfaction; compared to intramuscular interferon beta-1a, natalizumab was associated with more satisfaction with the ability of the drug to treat or prevent MS and was considered more convenient; natalizumab was considered easier to use than either form of interferon beta or glatiramer acetate; intramuscular interferon beta-1a was associated with less satisfaction with ease of planning than the other drugs; and for subcutaneous interferon beta-1a and glatiramer acetate, lower convenience scores were linked with reduced adherence

Company-sponsored, retrospective study to compare persistence with and adherence to fingolimod versus glatiramer acetate, interferon, and natalizumab using administrative claims data from the US PharMetrics Plus database

Drug discontinuation rates were lower for fingolimod (27.9%) versus other therapies [glatiramer acetate (39.5%), interferons (43.7%), natalizumab (39.5%)]; fingolimod was also associated with a lower risk of non-adherence compared to the other therapies

Natalizumab was found to be more effective in this clinical practice setting than in pivotal trials; after followup, 68% (cumulative proportion) of participants were free of relapses, 93% were free of Expanded Disability Status Scale progression, 65% were free of combined clinical activity (that is, relapse or disease progression), 77% were free of MRI activity, and 53% were free of any disease activity

Study to examine whether any therapeutic approach that had been used (immunomodulating agents, other first-line therapies, fingolimod, or no treatment) had abolished MS disease recurrence after the discontinuation of natalizumab

Recurrence of disease activity (clinically or assessed by MRI) was similar among all groups (except that no disease reactivation occurred in an individual treated with 6 months with cyclophosphamide), indicating that current therapeutic strategies have no effect on disease reactivation after the discontinuation of natalizumab

Prospective, multicenter, observational study to examine the effects of natalizumab discontinuation versus continuation after 2 years of monthly treatments (24 doses, 300 mg each); individuals could choose to continue with natalizumab, start treatment with a different disease-modifying therapy, or stop therapy; the mean annualized relapse rate was the primary endpoint

; the Expanded Disability Status Scale scores were similar between the groups but the annualized relapse rate increased in those who did not continue natalizumab (0.17 in those who continued natalizumab versus 0.75 in those who stopped treatment and 0.56 in those who switched to a different treatment)

Company-sponsored, multicenter, prospective, observational, open-label study to examine the long-term safety and effectiveness of natalizumab (300 mg, given intravenously every 4 weeks); a primary objective is to examine the effect of natalizumab on Expanded Disability Status Scale (EDSS) scores over time

Individuals randomized to placebo or a different therapy versus natalizumab in earlier clinical trials displayed higher EDSS scores at baseline of this study and this effect continued to be apparent over 240 weeks; during the 240 week period EDSS scores were, in general, stable; individuals randomized to natalizumab in earlier trials displayed lower annualized relapse rates over the period of this study; individuals who received only 1 or 2 doses in a previous trial exhibited higher rates of hypersensitivity reactions and anti-natalizumab antibodies than participants in general; serious adverse events such as progressive multifocal leukoencephalopathy occurred in line with previous studies

Natalizumab was associated with a significantly reduced influence on outcome measures in individuals >50 years; 18.7% of these individuals halted natalizumab treatment because of lack of effect versus 7.7% of the younger individuals; this finding may be related to a negative association between inflammation and age

The annual relapse rate increased during the first year after the switch to fingolimod; an increased risk of relapses was predicted by an Expanded Disability Status Scale score >3 during the switching period

Observational study to examine the effects of natalizumab versus fingolimod on time to first relapse (primary outcome) and time to relapse or gadolinium-enhancing lesion (secondary outcome) when JC virus serology was used as the basis for selecting treatment

Company-sponsored, retrospective study to compare use of healthcare resources and proxy measures of relapse (from administrative claims data from the US PharMetrics Plus database) in individuals who had switched to natalizumab or fingolimod from another disease-modifying therapy (DMT)

In a real-world setting, both fingolimod and natalizumab reduced the use of healthcare resources as compared to use in the pre-index period and were associated with statistically similar likelihoods of relapses in the post-index period (as assessed by database claims); 68.1% of the fingolimod cohort and 68.6% of the natalizumab cohort were free of relapses in the post-index period

For the whole group, the annualized relapse rate was 0.94 before natalizumab therapy began, 0.47 during therapy, 0.63 during months 1 to 6 after cessation, and 0.55 during months 7 to 12 after cessation; in contrast, 22% of participants displayed higher individual relapse rates after versus before treatment (that is, rebound activity)

Discontinuation was followed by rebound disease activity in 11.9% of the individuals, who were more likely to have low disease activity before natalizumab treatment as well as a longer gap before beginning an alternative treatment

Open-label, proof-of-concept study to investigate the effects of natalizumab on levels of cerebrospinal fluid (CSF) osteopontin, a biomarker of intrathecal inflammation (primary endpoint), and other CSF biomarkers of inflammation and axonal damage

Survey-based, observational, multicenter, cohort study of individuals undergoing a planned switch from natalizumab to fingolimod to examine the relapse frequency during the washout period and the initial period of fingolimod treatment

Switching from natalizumab to fingolimod was linked with a risk of relapse during the washout period or during the early stages of fingolimod treatment; washout periods <3 months were associated with reduced risk of relapse

Analysis of administrative claims (using the Truven Health MarketScan Databases) to compare health care use and costs related to MS before and after beginning natalizumab treatment in the US using paired statistical tests

Natalizumab use was associated with a reduction in the fraction of individuals with inpatient stays related to MS, the length of inpatient stays, and inpatient costs, as well as a reduction in corticosteroid use; these reductions were seen even if other disease-modifying treatment (DMT) had been used in the previous year, although greater reductions occurred if no other DMTs had been used

Study to evaluate the net risks and benefits of natalizumab versus fingolimod, interferon beta, or no treatment over sub-groups with different progressive multifocal leukoencephalopathy (PML) risk; a Markov cohort model was designed to examine the effects of treatment on quality-adjusted life years

Industry-funded, multicenter, open-label, single-arm, observational study to examine changes in fatigue and cognition associated with natalizumab treatment, with the primary endpoint the change in the Visual Analog Scale for Fatigue score over 12 weeks

Systematic review of published randomized, controlled clinical trials to compare the effects of dimethyl fumarate to those of existing disease-modifying treatments; relative effect sizes were derived from mixed treatment comparisons

Dimethyl fumarate (240 mg twice a day) was associated with a greater reduction in the annualized relapse rate (ARR) than placebo, interferon beta-1a, interferon beta-1b, glatiramer acetate, and teriflunomide (7 mg and 14 mg doses); dimethyl fumarate and fingolimod showed similar effects on the ARR; natalizumab was associated with a greater reduction in the ARR than dimethyl fumarate; dimethyl fumarate was associated with favorable safety outcomes; variability in how outcomes were defined and in the heterogeneity of enrolled individuals in the included trials were limitations of this review

Most individuals (92.8%) began treatment with either interferon beta or glatiramer acetate, but individuals who began treatment with natalizumab were more likely to continue with that treatment (32.3% versus 16.9%) and were less likely to have a treatment gap or switch treatments

DMTs were associated with increased cardiovascular risk factors, such as increased diastolic blood pressure; as compared with a lack of DMT, interferon beta-1b and glatiramer acetate were associated with higher risk and natalizumab with lower risk; additionally, cardiovascular drugs in DMT-naïve individuals were associated with increased MS severity

Analysis of data from the MSBase Registry to (i) determine the effect of switching from natalizumab to fingolimod on the annualized relapse rate (ARR); (ii) compare the experience of switching from natalizumab to fingolimod to that of switching from interferon beta/glatiramer acetate or no previous treatment to fingolimod; and (iii) examine factors that predict time to first relapse on fingolimod

Switching from natalizumab to fingolimod resulted in an increased ARR (from 0.26 to 0.38); prior relapse activity was the best predictor of relapse on fingolimod; relapse rates were not increased in individuals switching from natalizumab to fingolimod versus those switching from other treatments; and washout periods of more than 2 months were associated with a higher risk of relapse

Observational study to examine changes in grey and white matter volume in the brain in individuals treated with natalizumab, with MRI scans at baseline, 12 months, and 24 months; study was motivated by clinical trial results showing an association between natalizumab and brain volume loss after the initial year of treatment, probably a result of pseudoatrophy

Early loss of brain volume associated with natalizumab therapy was found to be primarily caused by loss of white matter volume, which is related to the presence of active lesions at the beginning of therapy

Natalizumab reduced plasma levels of osteopontin (which are increased in individuals with RRMS versus healthy controls), cognitive impairment, and fatigue; whereas baseline osteopontin and cognitive impairment levels were correlated, as were the decreases in osteopontin and cognitive impairment during treatment, osteopontin levels and fatigue were not correlated either before or during treatment